ABSTRACT Globally, liver cancer is the 2nd leading cause of cancer death in men and the 6th leading cause in women. Alcohol abuse represents one of the major risk factors for liver cancer along with HCV/HBV infection and obesity. Evidence suggests that alcohol promotes hepatocarcinogenesis by increasing hepatocyte proliferation via activation of Wnt/?-catenin signaling and consequent induction of ?classical? Wnt target genes. However, the mechanisms by which other ?non-classical? Wnt targets mediate alcohol-promoted HCC remain largely unknown. To this end, we have discovered that stearoyl-CoA desaturase 2 (Scd2) is a novel ?non-classical? Wnt/?-catenin target gene which is upregulated and required for the expression of co-receptor LRP5/6 and tumorigenic activity of liver tumor-initiating stem-like cells (TICs) isolated from HCV-induced and alcohol-promoted HCC in mice and human HCC cell lines. Further, our results demonstrate this Wnt-SCD-LRP5/6 positive loop involves SCD's ability to stabilize LRP5/6 mRNA via the 3'UTR AU-rich element (ARE) binding protein HuR which is also known for its ability to upregulate proinflammatory and tumor-promoter genes. Thus, we hypothesize that SCD enhances alcohol-promoted liver tumorigenesis through a positive feedback loop for canonical Wnt signaling via HuR-mediated LRP5/6 expression. To advance this hypothesis we will address the following aims as part of my K08 mentored research training toward academic independence: Aim 1: to determine the mechanism and significance of SCD-dependent, HuR-mediated LRP5/6 expression in alcohol-promoted liver tumorigenesis by investigating: 1) how SCD inhibition or knockdown (KD) reduces cytoplasmic HuR in TICs and Huh7 cells; and 2) whether ectopic LRP6 expression rescues the anti-tumorigenic effects of Scd2 KD in TICs in vitro and in orthotopically transplanted immune-competent B6 mice fed alcohol. Aim 2: to perform integrated bioinformatics analysis to determine whether expression of SCD, LRP5/6 and HuR per microarray analysis and desaturation of fatty acids per lipidomic analysis are associated with HCC and poor prognosis in three HCC patient cohorts. Aim 3: to determine whether hepatocyte-specific Scd2 ablation suppresses DEN-initiated and alcohol-promoted development of liver tumors in mice by using Albumin-Cre or AAV8-Ttr-Cre mediated liver-specific ablation of Scd2 in Scd2flox/flox mice.